Microtubules are composed of dynamic polymers of tubulin which are involved in various cellular processes such as cell division and cell shape, especially in induction of apoptosis. Rapidly dividing cells are more susceptible to tubulin polymerization inhibitors than non-dividing cells and impair microtubule dynamics and consequently arrest cells during mitosis (Jordan, M. A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Med. Res. Rev., 1998, 18, 259-296). The mode of action of tubulin inhibitors is that they bind to the tubulin binding sites thereby stabilizing or destabilizing microtubule assembly. Disruption of microtubule leads to cell cycle arrest at G2/M phase followed by apoptotic cell death (Pasquier, E.; Kavallaris, M. IUBMB Life., 2008, 60, 165-170).
Combretastatins are a class of naturally occurring compounds isolated from the African willow tree combretum caffrum has shown considerable interest and shown to be potent tubulin inhibitor and attracted the medicinal chemists in the design of various combretastatins analogs (Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C. M.; Alberts, D. S.; Garcia Kendall, D. Experientia 1989, 45, 209). Combretastatin A-4 (1) a simple cis stilbene has been reported to exhibit potent cytotoxicity against various cancer cell lines including multi drug resistant cells exhibiting excellent anticancer activity and found to be inhibit polymerization of tubulin by binding to the colchicine site. But CA-4 failed to show in vivo efficacy due to its poor water solubility and its pro drug of CA-4 disodium phosphate derivative (CA-4P) exhibiting promising results and presently in clinical trails (Buolamwini, J. K. Curr. Opin. Chem. Biol., 1999, 3, 500-509). The structure-activity relationship (SAR) information confirmed the importance of cis-stereochemistry and trimethoxy substituents in the A-ring and a new combretastatin derivatives with B-ring modifications by replacement of phenyl group with benzo[b]thiophene and benzofuran combretastatin analogues (ST2151) and (ST2179) and their phosphate prodrugs were synthesized and exhibiting high antitumor activity in both in vitro and in vivo models (Simoni, D.; Romagnoli, R.; Baruchello, R.; Rondanin, R.; Rizzi, M.; Pavani, M. G.; Alloatti, D.; Giannini, G.; Marcellini, M.; Riccioni, T.; Castorina, M.; Guglielmi, M. B.; Bucci, F.; Carminati, P.; Pisano, C. J. Med. Chem. 2006, 49, 3143-3152). Various series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) furnished various novel heterocyclic CA-4 analogues. These compound showing anticancer activity and also antitubulin activity in a variety of tumor models while retaining the characteristics of CA-4. These compounds include where tetrazole ring could replace the cis double bond to maintain potent cytotoxicity. All these compounds showed excellent antitumor activities against the colon 26 murine tumors when given intravenously (Ohsumi, K.; Hatanaka, T.; Fujita, K.; Nakagawa, R.; Fukuda, Y.; Nihei, Y.; Suga, Y.; Morinaga, Y.; Akiyama, Y.; Tsuji, T. Bioorg. Med. Chem. Lett. 1998, 8, 3153). Moreover a novel series of compounds consisting of 1,2- and 1,5 substituted five-membered aromatic heterocycles such as imidazole, oxazole, and pyrazole to mimic the cis double bond in CA-4 were synthesized particularly based on 1,5 diphenylsubstituted imidazoles (2) these compounds exhibited significant anticancer activity compared to that CA-4 (Wang, L.; Woods, K. W.; Li, Q.' Barr, K. J.; McCroskey, R. W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y. H.; Marsh, K.; Warner, R.; Lee, J. Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H. L. J. Med. Chem. 2002, 45, 1697-1711).
Benzothiazoles are a class of compounds comprising various activities including anticancer activity wherein 2-(4-Aminophenyl) benzothiazoles (3) and 2-(4-hydroxyphenyl) benzothiazoles are novel class of potent and selective antitumor agents and found to exhibit antitumor activity particularly against certain breast carcinoma cell lines MCF-7, MDA 468 with IC50<1 nM to be promising anticancer activity both in vitro and in vivo also (Shi, D. F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.; Lelieveld, P.; Fichtner, I.; Stevens, M. F. J. Med. Chem. 1996, 39, 3375-3384). Various fluorinated and 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole were reported to be anticancer agents and these compounds shown to exhibit potent and selective inhibitory activity against lung, colon, and breast cancer cell lines. (Hutchinson, A.; Chua, M.; Browne, H. L.; Trapani, V.; Bradshaw, T. D; Westwell, A. D; Stevens, M. F. J. Med. Chem. 2001, 44, 1446-1455” and “Mortimer, C. G.; Wells, G.; Crochard, J. P.; Stone, E. L.; Bradshaw, T. D.; Stevens, M. F.; Westwell, A. D. J. Med. Chem. 2006, 49, 179-185).
Keeping this aspect in mind, 2-phenyl benzothiazole linked imidazole compound were designed and synthesized comprising of 2-phenyl benzothiazoles and imidazole moiety by forming 1, 5 oriented 2-phenyl benzothiazole and various phenyl ring and also various heteroaromatic ring systems maintaining cis conformation which are expected to possess promising anticancer activity. Additionally, these are structurally simple small molecules.
